PROJECT SUMMARY The candidate, D. Clark Files, MD, is a critical care physician-scientist seeking a K08 Mentored Clinical Scientist Research Career Development Award to develop and apply his skills to assess the mechanisms underlying skeletal muscle wasting in older patients experiencing a critical illness, such as acute respiratory distress syndrome (ARDS) or sepsis. Dr. Files' career goal is to become an independent translational research leader focused on discovering mechanisms and developing therapies to reduce the morbidity and mortality of critical illnesses in older patients. The strategies outlined in this proposal provide the foundation to accomplish this goal. Skeletal muscle weakness has recently been identified as a major contributor to death and long-term disability from ARDS and sepsis. Older patients have increased mortality and muscle weakness from these conditions compared to younger patients. In order to understand these age-related differences in outcomes, the candidate developed mouse models of ARDS and sepsis in older animals, optimized for studying muscle function. In these models, older critically ill mice exhibit increased mortality and muscle wasting coupled to increased muscle proteolysis and impaired fatty acid metabolism. The goals of the studies outlined in the Research Plan (RP) are to identify mechanisms underlying these age-related differences and to attenuate muscle wasting in old critically ill mice through manipulation of the ubiquitin proteasome (UPP) and fatty acid oxidation pathways in skeletal muscle. To facilitate translation of these mechanisms into humans, the candidate will evaluate key mediators of these pathways in the muscles of patients with critical illness. The Career Development Plan (CDP) of this proposal outlines a detailed strategy for educational and experiential learning in the areas of muscle physiology and biology, metabolism, clinical research and leadership. The mentorship team, with individual strengths in each of these areas, seeks to facilitate development of Dr. Files' basic science skills in a translational context and provide the foundations for future clinical research to become an independent investigator in critical care research. Key institutional resources include the Wake Forest Critical Illness Injury and Recovery Research Center, the Wake Forest Claude D. Pepper Older Americans Independence Center, and the Wake Forest Bioenergetics Core Facility. In summary, execution of the RP and the CDP of this proposal will fill a gap in knowledge about the physical function impairment associated with post-intensive care syndrome and will position Dr. Files to become a leader in this important area of emerging research.